AB0122 ANTI-HISTONE AND ANTI-NUCLEOSOME ANTIBODIES, RATHER THAN ANTI-DSDNA ANTIBODIES ARE ASSOCIATED WITH INTERFERON-INDUCED BIOMARKERS IN SUDANESE AND SWEDISH SLE PATIENTS
Authors: S. Elbagir, N. A. Mohammed, V. Oke, A. Zickert, A. Larsson, J. Nilsson, A. Elshafie, A. Svanqvist, C. Westerberg, E. M. Elagib, M. A. M. Nur, I. Gunnarsson, E. Svenungsson, J. Rönnelid
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Antibodies against double stranded DNA (anti-dsDNA) can induce production of interferon-alpha and other cytokines after forming immune complexes. In SLE, anti-dsDNA often exists together with autoantibodies against other chromatin components, like histones and nucleosomes. These antibodies are known to characterize a SLE subgroup with early disease onset and increased occurrence of nephritis. <h3>Objectives</h3> We investigated how anti-nuclear autoantibody (ANA) specificities associate with pro-inflammatory cytokines in two ethnically different cohorts of SLE patients, from Sudan and Sweden. <h3>Methods</h3> We included 93 Sudanese and 480 Swedish SLE patients. Serum levels of autoantibodies against dsDNA, Sm, the Sm/U1RNP complex, U1RNP, SSA/Ro52, SSA/Ro60, SSB/La, ribosomal P, PCNA and histones were quantified with a bead-based multiplex immunoassay; with positive reactions determined as above the 98<sup>th</sup> percentile among respective national controls. In the Swedish cohort another bead-based multiplexed immunoassay including anti-nucleosome antibodies was also used. Relative levels of 73 plasma biomarkers were determined with Proximity Extension Assay technique except for Interferon gamma-induced protein (IP-10) in the Swedish cohort that was quantified by ELISA. Adjusted p values were considered significant when &lt;0.05. <h3>Results</h3> Among Sudanese patients, levels of 5/73 biomarkers showed significant associations to ANA-associated antibodies. Anti-histone antibodies showed the strongest positive correlations with interferon-inducible factors (monocyte chemoattractant protein [MCP-1] and IP-10), monocyte chemoattractant protein-3 (MCP-3) and S100 calcium-binding protein A12 (S100A12), and negative correlation with stem cell factor (SCF); R<sup>2</sup>(P values) were 0.15(0.04), 0.18(0.008), 25(0.0001), 0.13(0.04) and 0.31(&lt;0.0001) respectively. Biomarker associations remained significant for anti-histone antibody after adjustment for age and sex. Also, anti-dsDNA antibodies associated with MCP-3 (0.13(0.04)), IP-10 (0.13(0.03)) and S100A12 (0.13(0.04)), but when combining with anti-histone in the same regression model, anti-dsDNA associations were lost while anti-histone antibodies remained. Positive associations with lower R<sup>2</sup> values were found also for anti-ribosomal P antibodies with MCP-1, MCP-2 and C-C motif ligand 19 (CCL-19), and for anti-Sm with IP-10. Validation analysis among Swedish patients for MCP-1, IP-10, SA100A12 also demonstrated significantly stronger associations to anti-histone and anti-nucleosome antibodies compared to anti-dsDNA and other ANA specificities, and in combined regression models, anti-dsDNA either became non-significant or considerably less significant than anti-histone/nucleosome antibodies. When excluding anti-histone or anti-nucleosome positive patients, the associations between interferon-inducible factors MCP-1/IP-10 and anti-dsDNA were lost. In contrary, when excluding anti-dsDNA positive patients, associations with anti-histone and anti-nucleosome remained significant. SA100A12 associations with anti-dsDNA antibodies remained significant after exclusion of anti-histone positive patients, but were lost when excluding anti-nucleosome positive patients. <h3>Conclusion</h3> Using uni- and multi-variate analyses as well as patient stratification, levels of mainly IFN-induced inflammatory biomarkers correlate strongest with anti-histone and anti-nucleosome antibodies compared to other ANA specificities including anti-dsDNA. Our results, from two lupus cohorts with different ethnicities, suggest that autoantibodies against DNA-complexes or DNA-associated proteins rather than anti-dsDNA antibodies per se may drive the induction of the interferon signature in SLE. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.